This invention relates to substituted naphthalenylsulfonylimidazolidinediones and their thioxo analogs, to processes for their preparation, to methods for using the compounds, and to pharmaceutical preparations thereof. The compounds have pharmaceutical properties which render them beneficial for the treatment of diabetes mellitus and associated conditions.
For many years diabetes mellitus has been treated with two established types of drugs, namely insulin and oral hypoglycemic agents. These drugs have benefited hundreds of thousands of diabetics by improving their well-being and prolonging their lives. However, the resulting longevity of diabetic patients has led to complications such as neuropathy, nephropathy, retinopathy, cataracts and atherosclerosis. These complications have been linked to the undesirable accumulation of sorbitol in diabetic tissue, which in turn resulted from the high levels of glucose characteristic of the diabetic patient.
In mammals, including humans, the key enzyme involved in the conversion of hexoses to polyols (e.g. the sorbitol pathway) is aldose reductase. J. H. Kinoshita and collaborators [see J. H. Kinoshita et al, Biochem. Biophys. Acta, 158, 472 (1968) and references cited therein] have demonstrated that aldose reductase plays a central role in the etiology of galactosemic cataracts by effecting the conversion of galactose to dulcitol (galactitol) and that an agent capable of inhibiting aldose reductase can prevent the detrimental accumulation of dulcitol in the lens. Furthermore, a relationship between elevated levels of glucose and an undesirable accumulation of sorbitol has been demonstrated in the lens, peripheral nervous cord and kidney of diabetic animals, see A. Pirie and R. van Heyningen, Exp. Eye Res., 3, 124 (1964); L. T. Chylack and J. H. Kinoshita, Invest. Ophthal., 8, 401 (1969) and J. D. Ward and R. W. R. Baker, Diabetol., 6, 531 (1970).
The relevant prior art is as follows.
K. Sestanj, et al, U.S. Pat. No. 4,568,693, Feb. 4, 1986, disclose N-naphthoylglycine derivatives effective as aldose reductase inhibitors. J. Okuda et al, Japanese Patent No. 58/109-418-A (1981); K. Inagaki et al, Chem. Pharm. Bull., 30(9), 3244-3254 (1982); I. Miwa, et al, Chem. Pharm. Bull., 32(5), 2030-2032 (1984); and J. Okuda, et al, Chem. Pharm. Bull., 33(7), 2990-2995 (1985) disclose 1-(phenylsulphonyl)hydantoins useful as aldose reductase inhibitors. V. G. Zubenko, et al, Farmatsevt Zh. (Kiev) 16(2), 10-15 (1961) disclose derivatives of azolidine useful as antidiabetic compounds. I. S. Bengelsdorf, J. Am. Chem. Soc., 75, 3138-3140 (1953) discloses preparation of benzenesulfonylhydantoins.
Japanese patent application publication number Ja.15187/68 discloses sulfonyl hydantoin derivatives substituted on the carbon atom of the hydantoin ring. These compounds have anti-convulsant activity.
The present application discloses novel substituted naphthalenylsulfonylimidazolidinediones and their thioxo analogs represented below by formula (I), which are more effective inhibitors of aldose reductase than the reported benzenesulfonylhydantoins. They are useful for the treatment of conditions associated with diabetes mellitus such as neuropathy, retinopathy, nephropathy, cataracts and atherosclerosis. The compounds of formula (I) below increase visual acuity. These compounds show hypoglycemic activity and are useful in the treatment of some forms of diabetes. They also stabilize the weight of the subject by inhibiting weight gain. These compounds are also useful for the treatment of cardiac autonomic dysfunction and for lowering blood pressure.
These compounds are free of central nervous system side effects such as anti-convulsant activity.